tbuckley/cabot-search huggingface dataset:
Association of PIWI-interacting RNA-23210 with tumor metastasis in esophageal squamous cell carcinoma.
Authors: Wei Peng, Jinghua Zhu, Guochun Cao, Qin Zhang
Journal: Journal of Clinical Oncology (2023)

e16060 Background: his study aimed to analyze the expression, clinical significance of PIWI-interacting RNA-23210 (piRNA-23210) in esophageal squamous cell carcinoma (ESCC) and the biological effect in its cell line by piRNA-23210 overexpression. Methods: Quantitative real-time RT-PCR (qRT-PCR) was used to analyze piRNA-23210 expression in 60 cases of ESCC and 60 cases of normal tissues to study the relationship between piRNA-23210 expression and clinical factors. Recombinant lentiviral vector was constructed to overexpress piRNA-23210 and then infect ESCC TE-1 cell line. qRT-PCR was used to detect the level of piRNA-23210. 3-[4,5-dimethylthiazol -2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, cell apoptosis, cell cycle, and migration and invasion assays were also conducted as to the influence of the upregulated expression of piRNA-23210 that might be found on TE-1 cells biological effect. Results: The level of piRNA-23210 expression was found to be significantly lower in ESCC tissue than normal tissues (P &lt; 0.05). Decreased expression of piRNA-23210 was significantly correlated with lymph node metastasis, clinic stage, and histological grade of patients with ESCC (P &lt; 0.05). Meanwhile, loss of piRNA-23210 expression correlated significantly with poor overall survival time by Kaplan–Meier analysis (P &lt; 0.05). The result of biological function show that TE-1 cell transfected piRNA-23210 had a lower survival fraction; higher percentage of the G0/G1 phases; higher cell apoptosis; significant decrease in migration and invasion; and lower cyclin D1, Bcl-2, and MMP-7 protein expression compared with TE-1 cell untransfected piRNA-23210 (P &lt; 0.05). Conclusions: piRNA-23210 expression decreased in ESCC and correlated significantly with lymph node metastasis, clinical stage, poor overall survival, cell proliferation, cell cycles, cell apoptosis and migration and invasion in ESCC cell by regulating cyclinD1, Bcl-2, and MMP-7 expression, suggesting that piRNA-23210 may play important roles as a negative regulator to ESCC cell.
A phase 2 open-label study of conditionally active biologic ozuriftamab vedotin (BA3021) in failed PD-1/L1 treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Authors: Alan Loh Ho, Douglas Adkins, Jochen H. Lorch, Jacob Stephen Thomas, Jaspreet Singh Grewal
Journal: Journal of Clinical Oncology (2023)

TPS6107 Background: Ozuriftamab vedotin (BA3021) is a conditionally active biologic (CAB) anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) using a cleavable linker (CAB ROR2 ADC) (Short, et al., 2014, Chang, et al. 2021). Conditional and reversible binding by CABs is designed to reduce off-tumor toxicity and immunogenicity, avoid tissue-mediated drug deposition, and improve pharmacokinetics (PK). ROR2 is a cell-surface transmembrane receptor protein tyrosine kinase highly expressed in several tumor types including head and neck squamous cell cancer (HNSCC). Increased ROR2 expression has been associated with tumor resistance to chemotherapy, programmed death-1 (PD-1) inhibitors, molecular targeted therapy, and radiation therapy. A pronounced unmet need exists as the majority of patients with recurrent or metastatic HNSCC experience disease progression with existing therapies (Chow 2020). Methods: BA3021-002 is a multi-center, open-label, single-arm Phase 2 study (n=40) designed to evaluate the efficacy and safety of BA3021 in patients previously treated with PD-(L)1 with ROR-2 expressing recurrent or metastatic HNSCC. Eligible patients include those with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria. Failure to prior treatment is defined as documented disease progression after no more than one PD-1/L1 inhibitor either administered as monotherapy or in combination therapy. Pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and biomarker assessments will be performed. Enrollment is ongoing (NCT05271604) References: Chang, H.W., Frey, G., Liu, H., Steinman, L., Boyle, W.J. and Short, J.M. Proc. Natl. Acad. Sci. 2021 Mar. 2; 118(9). Chow LQ. Head and neck cancer. N Engl J Med. 2020 Jan 2;382(1):60–72. doi: 10.1056/NEJMra1715715. Short, J.M. Nature Biotechnology 2014 Nov 8, 13(20). Clinical trial information: NCT05271604 .
Efficacy and safety of IBI351 (GFH925) monotherapy in metastatic colorectal cancer harboring KRAS<sup>G12C</sup> mutation: Preliminary results from a pooled analysis of two phase I studies.
Authors: Ying Yuan, Yanhong Deng, Yongdong Jin, Yueyin Pan, Cunji Wang, Zhiwu Wang, Zhiye Zhang, Xiangjiao Meng, Yi Hu, Mingfang Zhao, Huijuan Wang, Nong Yang, Dongde Wu, Xiaorong Dong, Dingzhi Huang, Meili Sun, Lian Liu, Dong Hua, Zengqing Guo, Ke-Feng Ding
Journal: Journal of Clinical Oncology (2023)

3586 Background: IBI351 (GFH925) is an irreversibly covalent inhibitor of KRAS G12C and has demonstrated promising anti-tumor activity with acceptable safety in advanced solid tumors. Here, we report a pooled analysis of two phase I studies (NCT05005234, NCT05497336) evaluating the efficacy and safety of IBI351 (GFH925) monotherapy for metastatic colorectal cancer (CRC) harboring KRAS G12C mutation. Methods: Eligible metastatic CRC patients (pts) with KRAS G12C mutation were included. Pts received IBI351 (GFH925) orally at dose levels of 700mg once daily (QD), or 450/600/750mg twice daily (BID). The primary endpoint was objective response rate (ORR) assessed by investigator per RECIST v1.1. Data cutoff for the analyses was November 30, 2022 unless otherwise specified. Results: A total of 45 pts were enrolled (median age: 58.0 years; male: 57.8%; ECOG PS 1: 71.1%; pts with ≥2 prior lines of treatment: 66.7%), including 3, 4, 37, and 1 pts in 700mg QD, 450mg BID, 600mg BID, and 750mg BID cohorts, respectively. The median exposure to therapy was 84 days (range, 7-286), and 36 pts (80.0%) were still on treatment including one patient at 450mg BID with treatment exposure for 286 days. As of December 15, 2022, ORR was 47.5% (19/40, 95% CI: 31.5%-63.9%) and disease control rate (DCR) was 85.0% (95% CI: 70.2%-94.3%) for the efficacy-evaluable pts across all dose levels. The median duration of response (DOR) was not reached. For 32 efficacy-evaluable patients at 600mg BID, ORR and DCR were 43.8% (14/32) and 87.5%, respectively. Treatment-related adverse events (TRAEs) occurred in 40 (88.9%) pts, with the most common being anaemia, white blood cell count decreased, alanine aminotransferase increased, and pruritus. Grade ≥ 3 TRAEs occurred in 9 (20.0%) pts. No drug-related adverse events leading to treatment discontinuation or death occurred. Conclusions: IBI351 (GFH925) monotherapy demonstrated promising anti-tumor activity with manageable safety profile in metastatic CRC patients harboring KRAS G12C mutation. These two studies are still ongoing and longer follow-up will provide more solid evidence. Updated data will be presented at the meeting. Clinical trial information: NCT05005234 , NCT05497336 .
An open-label clinical trial of RP2 and RP3 oncolytic immunotherapy in combination with atezolizumab and bevacizumab for the treatment of patients with advanced colorectal carcinoma.
Authors: Dale Randall Shepard, Muneeb Ahmed, Tanios S. Bekaii-Saab, Johannes Wolff
Journal: Journal of Clinical Oncology (2023)

TPS3628 Background: Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality worldwide. PD-1/PD-L1 inhibition, in combination with other modalities, has demonstrated significant benefit in patients (pts) with microsatellite instability-high or mismatch repair deficient CRC. However, these agents have limited, if any, clinical benefit in pts with microsatellite stable (MSS) or mismatch repair proficient (pMMR) CRC. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 which expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), granulocyte-macrophage colony-stimulating factor (GM-CSF), and an anti–CTLA-4 antibody-like molecule; RP3 additionally expresses 4-1BB and CD40 activating ligands, but does not express GM-CSF. Both agents have demonstrated preliminary safety and efficacy in pts with solid tumors. This study will evaluate the safety and efficacy of RP2 and RP3 in combination with atezolizumab (Atezo) and bevacizumab (Bev) in pts with advanced MSS and pMMR CRC. Methods: Pts with a histologic diagnosis of unresectable and/or metastatic CRC, with documented MSS or pMMR status, and previously treated with up to 3 standard-of-care systemic regimens will be enrolled in the RP2 + Atezo + Bev or RP3 + Atezo + Bev treatment groups (30 pts per group). Further key inclusion criteria include Eastern Cooperative Oncology Group performance status 0–1 and adequate hepatic, renal, and hematologic function. RP2/RP3 will be injected into tumors by direct (including via colonoscope) or image-guided injection. Pts will receive 8 total doses of up to 10 mL of RP2 or RP3, with a first dose concentration of 1 × 10 6 plaque-forming units (PFU)/mL, followed by 3 doses of 1 × 10 7 PFU/mL every 2 weeks, and then 4 doses of 1 × 10 7 PFU/mL every 3 weeks. Pts may receive a second course of up to 8 injections of RP2/RP3 if study criteria are met. Bev will be administered starting on day 1 (with first dose of RP2/RP3); Atezo will be administered starting week 7 on the same days as RP2/RP3. The primary endpoint is objective response rate; secondary endpoints are safety, overall survival, progression-free survival, duration of response, and complete response rate. Antitumor activity will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 as modified for this study. Safety will be assessed by physical examination, clinical laboratory evaluations, vital signs, and monitoring for adverse events (AEs; including serious AEs). Clinical trial information: NCT05733611 .
Novel peptide binder to Glypican-3 for targeted radiopharmaceutical therapy of hepatocellular carcinoma.
Authors: Gary Li, Fanching Lin, Renee Clift, Takeru Ehara, Hayato Yanagida, Steven Horton, Katrina Salvador, Samantha Richardson, Matt Guest, Alain Noncovich, Abhijit Bhat, Guangzhou Han
Journal: Journal of Clinical Oncology (2023)

e16131 Background: Glypican-3 (GPC3) is a membrane-associated heparan sulfate proteoglycan primarily involved in embryonic development, and is barely detectable in normal adult tissues. Significant upregulation of GPC3 protein in hepatocellular carcinomas (HCC) has been observed in multiple immunohistochemistry (IHC) studies with up to 75% positivity rate, and is associated with poor prognosis. GPC3 is not expressed in healthy or non-malignant liver tissue. Targeting GPC3 could fulfill an unmet medical need for HCC, a leading cause of cancer-related deaths worldwide for which efficacious therapies are lacking. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for GPC3-targeted radiopharmaceutical therapy (RPT) to treat HCC. Methods: RAYZ-8009 is comprised of a novel macrocyclic peptide binder to GPC3, a linker, and chelator DOTA that can be complexed with different radioisotopes. The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR), as well as a radioligand binding assay in human HCC cell line HepG2. The cross-species binding was assessed by radioligand binding using recombinant mouse, cynomolgus monkey, and human GPC3 proteins. Target-mediated internalization in HepG2 cells was measured using Microbeta at various time points. In vivo biodistribution with 177 Lu, and anti-tumor efficacy studies using 225 Ac were performed in HepG2 tumor-bearing athymic nude mice. Results: RAYZ-8009 showed high binding affinity to human GPC3 with a K D of 0.7 nM as determined by SPR. Binding affinity was maintained across mouse, cynomolgus monkey and human GPC3. Potent cellular binding was confirmed in GPC3+ HepG2 cells, and was independent of choice of isotope. 177 Lu-RAYZ-8009 showed fast and efficient internalization with 42% internalized by 20 minutes in HepG2 cells. In vivo biodistribution of 177 Lu-RAYZ-8009 showed tumor uptake of 19.8, 16.6, 16.4, and 8.8 %ID/g at 2, 24, 48, and 96 hours, respectively. Renal uptake was 16.1, 4.7, 1.6, and 0.7 %ID/g at the same timepoints, with tumor/kidney ratios of 1.3, 3.7, 11.3, and 15.0, respectively. Minimal uptake was observed in other normal tissues. Tumor-specific uptake and retention were also observed when tumors were implanted orthotopically with no uptake in non-malignant liver tissue. Furthermore, significant tumor growth inhibition and survival benefit were achieved with 225 Ac-RAYZ-8009 in GPC3+ HCC xenografts. Conclusions: Preclinical pharmacodynamic, pharmacokinetic, biodistribution and efficacy data demonstrate the potential of RAYZ-8009 as a RPT agent for the treatment of patients with GPC3-positive HCC.
Interim analysis examining the feasibility of incorporating laser microdissection enrichment of tumor specimens and reverse phase protein array analysis with next generation sequencing into a molecular tumor board.
Authors: Timothy Lewis Cannon, Jamie Randall, Allison L. Hunt, Aratara Nutcharoen, John F. Deeken, Nicholas W. Bateman, Brian Corgiat, Justin B Davis, Emanuel Petricoin, Thomas P. Conrads
Journal: Journal of Clinical Oncology (2023)

e15068 Background: Since next generation sequencing (NGS) based profiling does not provide measures of protein abundance or activation state, clinical integration of reverse phase protein array (RPPA) with NGS could be useful for improving selection of targeted cancer therapy. We incorporated biopsy testing and proteogenomic analyses in an institutional Molecular Tumor Board (MTB) for cancer patients using CLIA-certified commercially available multi-omic platforms, including a commercially available CLIA RPPA functional protein drug target activation mapping platform. We present an interim analysis of our experience integrating functional phosphoprotein/protein based drug target activity data with NGS from 117 patients with metastatic solid tumors. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor biopsy specimens (n = 166) were obtained prospectively from patients as part of an IRB approved MTB. A representative H&amp;E-stained tissue section for each specimen was reviewed by a board-certified surgical pathologist. Specimens with sufficient total tumor cellularity to achieve protein lysate input requirements for RPPA were thin sectioned onto laser microdissection (LMD) membrane slides for selective harvest of tumor epithelium by LMD and RPPA analysis. In parallel, specimens from each case were also submitted for NGS analysis. The multi-omic data for each patient was reviewed by a panel of clinicians and scientists as part of the Inova Institutional MTB for clinical decision-making. Results: Patient tissue specimens (median = 1 per patient; range 1-5) were reviewed to assess feasibility of enriching tumor areas via LMD prior to RPPA analysis. Specimens from 64/117 patients were used for LMD, RPPA, and NGS. 48/117 patients were dropped due to inadequate tumor cellularity, patient death, or referral cases with inadequate specimen. At this time, 7/117 patients remained in the consenting-LMD-RPPA workflow. The median time from patient consent to RPPA analysis completion was 47.4 days. During this period, specimens were outside of the standard hospital-NGS workflow (ie, utilized for sectioning and review for LMD-RPPA) for ~10 days (median). Integrated review of the RPPA and NGS data by the MTB supported a clinical recommendation change for 34/64 patients (53%) overall, with some dependency by primary disease site. Clinical trial information: U20-11-4308.Conclusions: Incorporation of RPPA analysis of LMD enriched tumor samples with NGS was feasible in this pan-cancer cohort, with the mean time to results being less than 7 weeks. RPPA data provided additional treatment considerations for 59% of patients, the outcomes for whom continue to be monitored. [Table: see text]
Immune checkpoint inhibitors therapy in advanced bladder carcinoma: A meta-analysis of phase III randomized controlled trials.
Authors: Rushin Patel, Akshit Chitkara, Zalak Patel, Mrunal Patel, Fnu Anamika, Shivang Trivedi, Bhuvaneswari Ramaswamy
Journal: Journal of Clinical Oncology (2023)

e16584 Background: Currently, platinum-based chemotherapy is the standard treatment for advanced bladder cancer. Immune checkpoint inhibitors (ICIs) have been evaluated in these patients with clinical trials. There is no meta-analysis available of phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in these patients. In this article, we write about the meta-analysis of ICIs use in advanced bladder cancer. Methods: Systemic searches of PubMed, Embase, the Cochrane Library, Google scholar, and ClinicalTrials.gov were searched for relevant studies with prespecified terms. We included only phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in patients with advanced bladder carcinoma. Outcomes studied were Overall survival (OS), Progression-free survival (PFS), Objective response rate (ORR), and Grade 3 or higher adverse events (AE). We used a random effects model via RevMan 5.4 software to perform the meta-analysis. Results: 8 phase III RCTs met the inclusion criteria with a total of 5041 patients (immune checkpoint inhibitors = 2481 patients, Chemotherapy/placebo = 2560 patients) and a median follow-up of 24 months. Compared to the chemotherapy/placebo group, immune checkpoint inhibitors showed higher OS [HR = 0.83 (0.73-0.93) P = 0.002]. No significant differences were observed in PFS [HR = 0.84(0.68-1.05) P = 0.13] and ORR [HR = 2.15(0.51-9.09) P = 0.30] between the two groups. Compared to the chemotherapy group, immune checkpoint inhibitors showed significantly fewer severe adverse events [HR = 0.21 (0.14-0.32) P &lt; 0.00001]. Conclusions: The use of immune checkpoint inhibitors in patients with advanced bladder carcinoma is associated with favorable overall survival and fewer severe adverse events. The two groups observed no significant differences between progression-free survival and objective response rates.
Impact of hospital volume and margin status on survival following radical hysterectomy: An expanded NCDB study.
Authors: Vasanti Jhaveri, Jean Paul Tanner, Jason L. Salemi, Mitchell Kamrava, Thomas Rutherford, John David, Matthew L Anderson
Journal: Journal of Clinical Oncology (2023)

e17527 Background: Use of a minimally invasive surgical (MIS) approach to manage early-stage cervical cancer has been previously associated with an elevated risk of disease recurrence and death. However, the reasons why MIS would lead to worse clinical outcomes remains unclear. Here, we sought to determine whether hospital surgical volume and surgical margin status contribute to worse outcomes previously reported for minimally invasive radical hysterectomy (RH-MIS). Methods: Demographic and outcome data for women diagnosed with an invasive carcinoma of the cervix (SCCa) between 2010 and 2015 were abstracted from the National Cancer Database (NCDB). Differences by surgery type were examined using chi-square test for categorical variables and independent samples t-test test for continuous variables. Surgical margin status was reported as either positive or negative according to the presence of malignancy. Overall survival was evaluated using the Kaplan-Meier method and multivariable Cox proportional hazards regression. Analyses were stratified by hospital volume. Low volume facilities were defined as institutions performing &lt;10 surgeries per year. Results: We identified a total of 5,090 women who underwent radical hysterectomy by either minimally invasive (n=2181) or open (n=2909) approach. Between 2010 and 2015, the proportion of radical hysterectomies performed by RH-MIS increased from 42.7% to 70.3% of all cases. In contrast to prior reports, 5-year survival among RH-MIS patients was significantly better compared to RH-open patients (92.5% vs. 90.8%, p=0.02). However, women who underwent RH-MIS were significant younger (45.6±12.3 v. 46.8±12.3 years, p&lt;0.001), more educated (p&lt;0.001), more likely to be White Non-Hispanic (p&lt;0.001) and diagnosed with earlier stage disease (p&lt;0.008). Women who underwent RH-MIS were also less likely to have positive surgical margins (2.2% v 3.5%, p=0.006). After accounting for these differences, there was no statistically significant difference in survival for women undergoing RH-MIS vs. RH-open (HR, 1.18; 95% CI: (0.96-1.45). Positive margin status was associated with worse survival only at low-volume hospitals (HR, 2.30; 95% CI: 1.09-11.31). However, no other association between hospital volume, surgical route, margin status and survival was observed. Curiously, survival for women diagnosed in 2012 (HR, 1.51; 95% CI, 1.05 – 2.17) and 2013 (HR, 1.49; 95% CI, 1.03-2.15) not other years was significantly worse when compared to 2015, regardless of surgical route. Conclusions: Positive surgical margins following radical hysterectomy appear to be most effectively addressed at high volume centers caring for women with cervical cancer. These observations underscore a national need for equitable access to radiation care for women being treated for early stage cervical cancer.